Lessons learned from unsolicited findings in clinical exome sequencing of 16,482 individuals.
Lessons learned from unsolicited findings in clinical exome sequencing of 16,482 individuals.
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DOI：
10.1038/s41431-021-00964-0
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Yntema HG
中科院分区：
文献类型：
--
作者：
van der Schoot V;Haer-Wigman L;Feenstra I;Tammer F;Oerlemans AJM;van Koolwijk MPA;van Agt F;Arens YHJM;Brunner HG;Vissers LELM;Yntema HG
非征集性发现（UF）是无意发现的，易患与临床问题无关的疾病。在临床实践中发现的UF的频率和性质在很大程度上仍未探索。我们在这里评估了在5年期间确定的UF，其中16，482名索引患者接受了临床全外显子组测序（WES）。在0.58%（95/16，482）的索引患者中确定了UF，表明临床WES中UF的总体频率较低。使用限制性疾病基因组（0.03%）识别出的UF少于使用全外显子组/孟德尔组分析（1.03%）。出于医疗可诉性的原因，UF被披露给95人中的86人。这些UF中只有61%存在于“ACMG 59”列表中列出的基因中，该列表代表美国医学遗传学学院建议UF披露的59个基因。其余39%分为四类：与“ACMG 59”列出的疾病相似的疾病（25%）;疾病表现可能受到影响的疾病（7%）;提供生殖选择的UF（2%）;以及具有药物遗传学意义的UF（5%）。因此，我们的经验表明，与“ACMG 59”上列出的基因相比，易患可采取医学行动的疾病的UF影响范围更广，主张预先定义的基因列表过于限制，并且UF可能需要对可采取医学行动性进行特别评估。虽然UF的识别和披露取决于当地政策，但我们的经验教训为临床外显子组测序中UF的性质和几率提供了基本的见解。
Unsolicited findings (UFs) are uncovered unintentionally and predispose to a disease unrelated to the clinical question. The frequency and nature of UFs uncovered in clinical practice remain largely unexplored. We here evaluated UFs identified during a 5-year period in which 16,482 index patients received clinical whole-exome sequencing (WES). UFs were identified in 0.58% (95/16,482) of index patients, indicating that the overall frequency of UFs in clinical WES is low. Fewer UFs were identified using restricted disease-gene panels (0.03%) than when using whole-exome/Mendeliome analysis (1.03%). The UF was disclosed to 86 of 95 individuals, for reasons of medical actionability. Only 61% of these UFs reside in a gene that is listed on the “ACMG59”-list, representing a list of 59 genes for which the American College of Medical Genetics recommends UF disclosure. The remaining 39% were grouped into four categories: disorders similar to “ACMG59”-listed disorders (25%); disorders for which disease manifestation could be influenced (7%); UFs providing reproductive options (2%); and UFs with pharmacogenetic implications (5%). Hence, our experience shows that UFs predisposing to medically actionable disorders affect a broader range of genes than listed on the “ACMG59”, advocating that a pre-defined gene list is too restrictive, and that UFs may require ad hoc evaluation of medical actionability. While both the identification and disclosure of UFs depend on local policy, our lessons learned provide general essential insight into the nature and odds of UFs in clinical exome sequencing.
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影响因子：
5.2
作者：
Haer-Wigman, Lonneke;van der Schoot, Vyne;Yntema, Helger G.
通讯作者：
Yntema, Helger G.
影响因子：
8.8
作者：
Thompson, Michelle L.;Finnila, Candice R.;Cooper, Gregory M.
通讯作者：
Cooper, Gregory M.
影响因子：
5.2
作者：
van der Schoot, Vyne;Viellevoije, Simone J.;Oerlemans, Anke J. M.
通讯作者：
Oerlemans, Anke J. M.
DOI：
10.1038/gim.2017.157
发表时间：
2018-03
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Ormondroyd E;Mackley MP;Blair E;Craft J;Knight JC;Taylor JC;Taylor J;Watkins H
通讯作者：
Watkins H
影响因子：
3.7
作者：
Olfson E;Cottrell CE;Davidson NO;Gurnett CA;Heusel JW;Stitziel NO;Chen LS;Hartz S;Nagarajan R;Saccone NL;Bierut LJ
通讯作者：
Bierut LJ